|Publication number||US4639365 A|
|Application number||US 06/662,075|
|Publication date||Jan 27, 1987|
|Filing date||Oct 18, 1984|
|Priority date||Oct 18, 1984|
|Also published as||EP0198051A1, WO1986002352A1|
|Publication number||06662075, 662075, US 4639365 A, US 4639365A, US-A-4639365, US4639365 A, US4639365A|
|Inventors||A. Dean Sherry|
|Original Assignee||The Board Of Regents, The University Of Texas System|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (22), Non-Patent Citations (12), Referenced by (118), Classifications (27), Legal Events (7) |
|External Links: USPTO, USPTO Assignment, Espacenet|
Gadolinium chelates as NMR contrast agents
US 4639365 A
Chelates of gadolinium with 1,4,7-triazacyclononane-N,N',N"-triacetate; 1,4,7,10-tetrazacyclododecane-N,N',N'"tetraacetate; and 1,5,9-triazacyclododecane-N,N',N"-triacetate are useful as NMR contrast agents.
1. A method of enhancing NMR contrast in a living subject, comprising administering internally to the subject an effective amount of a contrast agent which comprises a chelate of gadolinium with a compound selected from the group consisting of DOTRA, DOTA, NOTA, and salts thereof.
2. A method of enhancing NMR contrast in a living subject, comprising administering internally to the subject an effective amount of a contrast agent which comprises a chelate of gadolinium with DOTRA or a salt thereof.
3. A method of enhancing NMR contrast in a living subject, comprising administering internally to the subject an effective amount of a contrast agent which comprises a chelate of gadolinium with DOTA or a salt thereof.
4. A method of enhancing NMR contrast in a living subject, comprising administering internally to the subject an effective amount of a contrast agent which comprises a chelate of gadolinium with NOTA or a salt thereof.
BACKGROUND OF THE INVENTION
The present invention relates to NMR imaging of living subjects. More specifically, it relates to agents which can be used to enhance NMR contrast in such subjects.
Nuclear magnetic resonance (NMR) has been used for many years as a means of chemical analysis. NMR is a type of radio frequency spectroscopy which is based upon small energy differences between electrically charged atomic nuclei which are spinning parallel or antiparallel to an applied magnetic field. When radio frequency energy is applied to the sample, these spinning atomic nuclei change spin states and in doing so, absorb some of the radio frequency energy. Nuclei in slightly different chemical environments within the same molecule change spin state at slightly different energies and this produces characteristic absorptions or resonances which help identify the molecular structure.
NMR has more recently been used in examinations of the human body. Other methods such as computerized axial tomography (CAT scanning) have been used in the past for this purpose, and still are. However, because NMR does not use ionizing radiation, it is believed to have some safety advantages over CAT. Thus, NMR is an advantageous method of producing cross-sectional images of the human body.
The quality of the images obtained from an NMR scan are based on two properties: the proton densities of the various tissues and differences in proton relaxation rates. The proton density of tissues cannot be readily altered. Proton relaxation rates can be adjusted by adding a paramagnetic relaxation agent, more commonly known as a "contrast agent." Contrast agents enhance the contrast in NMR images between magnetically similar but histologically dissimilar tissues.
Gadolinium has been tested as a contrast agent in the past because it has a large magnetic moment, which efficiently relaxes magnetic nuclei. Gadolinium's strong paramagnetic properties are the result of its seven unpaired electrons.
One drawback of gadolinium as a contrast agent is its toxicity to animals. One possible remedy for this problem is to incorporate gadolinium in a compound that would pass through the body and be excreted without releasing toxic gadolinium ions. Unfortunately, the rare earth elements, such as gadolinium, do not form stable covalent bonds with organic molecules, so such molecules can decompose in vivo and release the toxic ions. Complexes of gadolinium might overcome this problem.
There is a need for effective contrast agents which avoid the toxicity problems inherent in using gadolinium.
SUMMARY OF THE INVENTION
The present invention concerns NMR contrast agents which include a chelate of gadolinium with either 1,4,7-triazacyclononane-N,N',N"-triacetate (NOTA), 1,4,7,10-tetrazacyclododecane-N,N',N",N'" tetracetate (DOTA), or 1,5,9-triazacyclododecane-N,N',N"-triacetate (DOTRA), or salts thereof. When the phrase "salts thereof" is used in this patent, it means that one of the acidic hydrogen ions on an acetate group has been replaced by another cation, not that an entire acetate group has been replaced. The particular juxtaposition of the nitrogen and oxygen atoms has an important effect on the chelating properties of NOTA, DOTA, and DOTRA, so removal of an entire acetate group would harm that property. Of course, upon dissolving the chelate in solution, the cation that has replaced a hydrogen ion would dissociate leaving the same central ionic species.
These contrast agents can be used to enhance NMR contrast in a living subject by administering internally to the subject an effective amount of the agent. "Administering internally" is intended to include methods such as injection, ingestion, or the like which would be known to one skilled in this field.
DOTRA, DOTA, and NOTA reduce or prevent the toxic effects of the Gd3+ cation to in vivo processes by firmly complexing with it. DOTRA and DOTA form gadolinium chelates that are especially stable, with NOTA binding somewhat less firmly, possibly due to the small size of the "hole" in NOTA's molecule.
This binding strength should result in very low biological toxicity for contrast agents in accordance with the present invention. In addition, the agents appear to have substantially better relaxation properties than some prior art agents, which will permit the use of a smaller amount of the agents to achieve the same effect.
DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION
The following is a procedure which can be used to synthesize NOTA:
Step 1: Synthesis of N,N',N"-tri(p-toluenesulfonyl)diethylene-triamine
A solution of p-toluenesulfonyl chloride (191 g) in ether (500 ml) was added drop by drop to a solution of diethylene triamine (38 ml) and sodium hydroxide (40 g) in water (250 ml). The mixture was stirred for one hour at room temperature. A white precipitate was formed and was collected by filtration, washed with water, and then recrystalized using methanol. (Acetonitrile could also be used). The melting point of the recrystalized precipitate was 174° to 175° C. The yield was 90%, and should always be above 70%.
Step 2: Synthesis of di(p-toluenesulfonyl)ethylene glycol
Twenty-eight ml of ethylene glycol and 100 ml of pyridine were added over a 2.5 hour period to a stirred mixture of tosyl chloride (210 g) in pyridine (225 ml), with the mixture being cooled by a water bath. After stirring for several hours, the mixture was shaken with one liter of ice water for about ten minutes and then filtered. The residue was washed with ether, dilute sulfuric acid, water, and finally ether. (Each of the washed liquids was ice cold.) The residue was then dried by vacuum pumping and recrystallized from boiling acetonitrile. The recrystallized residue, yield 75%, had a melting point of 123° to 125° C.
Step 3: Preparation of the disodiom salt of N,N',N"-tri(p-toluenesulfonyl)diethylene triamine
Each part of this step was conducted under a nitrogen atmosphere. 2.65 grams of sodium metal was weighed in hexane and placed in about 75 ml of pure ethanol. The sodium-ethanol reaction is highly exothermic, and the heat helps dissolve the sodium to give sodium ethoxide. A hot slurry of 1,4,7-tritosyl-1,4,7-triazaheptane (28.3 g) from Step 1 and 150 ml of ethanol was stirred in a reaction vessel with a reflux condenser. The slurry was heated to reflux using an oil bath, and then the sodium ethoxide was added as rapidly as possible. After continued stirring and flushing with nitrogen, a white solid precipitated. Slight heating and flushing continued until all the ethanol was removed and the dry disodium salt of 1,4,7-tritosyl-1,4,7-triazaheptane was left.
Step 4: Synthesis of 1,4,7-triazacyclononane-N,N',N"-tritosylate
This step was conducted without removing the dry salt from the Step 3 reaction vessel. The dry disodium salt was dissolved in 225 ml of dry dimethyl formamide (DMF), once again under a nitrogen atmosphere. The mixture was stirred and heated to 95° to 110° C. Next, a 0.2M solution of ethylene glycolditosylate (18.5 g) in DMF was added over a period of three hours. After one additional hour of stirring at 100° C., the mixture was cooled overnight. It was then concentrated by distillation under reduced pressure until precipitation began. The concentrate was poured into 500 mls of vigorously stirred water and filtered. The residue was washed with water, dried by vacuum pumping, and recrystallized from boiling acetone. The product, 1,4,7-triazacyclononane-N,N',N"-tritosylate, had a melting point of 217° to 220° C. and was present in a yield of 70%.
Step 5: Synthesis of 1,4,7-triazacyclononane trihydrobromide
One hundred twenty ml of a mixture of 47% HBr, 67 ml of glacial acetic acid, 13.99 g of the product of Step 4 were heated to 100° C., and the volume was then remeasured. The mixture was then refluxed for fifty hours and concentrated by atmospheric distillation to about 20% of the beginning volume. The concentrate was then filtered. The residue, containing 1,4,7-triazacyclononane-N,N',N"-trihydrobromide, was extracted into water and then recovered by evaporation in vacuo. The trihydrobromide was recrystallized from boiling hydrobromic acid. Its melting point was 280° C, and it was present in 70% yield. Tosylate groups were completely absent in the NMR spectra of the trihydrobromide.
Step 6: Synthesis of 1,4,7-triazacyclononane-N,N',N"-triacetete (NOTA)
A solution of 4.72 g of bromoacetic acid and 1.2 g of sodium hydroxide in 10 ml of water was added with stirring to a solution of 3.72 g of the product of Step 5 and 1.2 g of sodium hydroxide in 3.5 ml of water at about 20° C. The mixture was heated to 85° C. with an oil bath while being stirred, and then 1.2 g of sodium hydroxide, dissolved in 6.5 ml of H2 O, was added dropwise with stirring. The temperature was maintained between 80° to 90° C. for one and one-half hours. The contents of the flask were then cooled to room temperature and the pH was adjusted to about 3.5 with concentrated hydrobromic acid. 25 ml of ethyl alcohol was added, and the solution was stirred for an hour under refrigeration. A white crystalline precipitate formed which was filtered out, washed with pure ethanol, and dried in a vacuum oven at 70° C. overnight. This product was NOTA, and the 2.5 g of it represented an at least 70% yield.
Elemental analysis showed close correspondence to what was expected for C12 H21 O6 N3 (NaBr)3.3H2 O. Calculated: 25.58% C, 4.79% H, 7.46% N, 28.42% Br, and 8.17% Na. Found: 25.39% C, 4.89% H, 7.43% N, 28.44% Br, and 8.00% Na.
This synthesis can be summarized as shown below. ##STR1##
DOTA and DOTRA can be synthesized using generally the same procedure, but starting with triethylene tetraamine instead of diethylene triamine to synthesize DOTA and dipropylene triamine and 1,3 propanediol instead of diethylene triamine and ethylene glycol, respectively, for synthesizing DOTRA. The remaining reagents would be identical with only the stoichiometric quantities varying for DOTA.
Once DOTA, NOTA or DOTRA has been obtained in crystalline form, a measured amount of it is dissolved in water and an equimolar amount of a gadolinium salt, such as gadolinium chloride or gadolinium nitrate, is added to the solution. The Gd-NOTA complex forms spontaneously above pH 5 while the Gd-DOTA and Gd-DOTRA complexes are kinetically slower to form and may require heating to 80° C. for 30 minutes to increase the rate of chelation.
Salts of DOTA, NOTA and DOTRA could, of course, also be used, since the counter ions will dissociate in solution. What synthetic procedure is most convenient may dictate which salt to use. The meglumine salt of Gd-DOTA, Gd-NOTA or Gd-DOTRA is one which should be useful in contrast agent formulations.
The contrast agents could be formulated as a saline solution and packaged in bottles having a rubber septum across the opening to permit withdrawing the solution with a syringe.
Contrast agents in accordance with the present invention can be used with NMR apparatus which are well known to those skilled in this field. Examples of U.S. patents which disclose NMR apparatus are U.S. Pat. Nos. 4,374,360; 4,398,148; 4,409,550; 4,425,547; 4,442,404; and 4,450,408, all of which are incorporated herein by reference. NMR imaging should probably be done within a few hours after administering the contrast agent to the subject, since the agent should be excreted from the body fairly rapidly.
The preceding is intended to illustrate specific embodiments of the present invention, and not to be an exhaustive description of all possible embodiments. Those skilled in this field will recognize that certain modifications could be made.
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US3930867 *||Jan 7, 1974||Jan 6, 1976||E. I. Du Pont De Nemours And Company||Macrocyclic polyamines as sensitizers for silver halide emulsions|
|US3932451 *||Nov 27, 1973||Jan 13, 1976||E. I. Du Pont De Nemours & Company||1,4,7,10-Tetraazatetracyclo[5.5.1.04,13.010,13 ]tridecane and its conjugate acids|
|US3987128 *||Aug 22, 1975||Oct 19, 1976||E. I. Du Pont De Nemours And Company||Tetracyclic tetraamino phosphoranes and method of preparation|
|US3996276 *||Aug 22, 1975||Dec 7, 1976||E. I. Du Pont De Nemours And Company||Bicyclic and tricyclic phosphorous triamides|
|US4038312 *||Oct 7, 1976||Jul 26, 1977||E. I. Du Pont De Nemours And Company||Tricyclic phosphorous triamides|
|US4085106 *||Jan 7, 1976||Apr 18, 1978||E. I. Du Pont De Nemours And Company||Bicyclic and tricyclic trisaminomethanes|
|US4130715 *||Jan 26, 1978||Dec 19, 1978||E. I. Du Pont De Nemours And Company||Tricyclic trisaminomethanes|
|US4337154 *||Apr 1, 1980||Jun 29, 1982||Nippon Shokubai Kagaku Kogyo Co., Ltd.||Crosslinked composite semipermeable membrane|
|US4352751 *||Sep 10, 1979||Oct 5, 1982||Analytical Radiation Corporation||Species-linked diamine triacetic acids and their chelates|
|US4374360 *||May 29, 1980||Feb 15, 1983||Sepponen Raimo E||NMR Diagnosis apparatus|
|US4398148 *||Feb 2, 1981||Aug 9, 1983||Thomson - Csf||Electromagnetic coil system for examination of large objects by nuclear magnetic resonance and whole-body imaging machine using a system|
|US4409550 *||May 15, 1981||Oct 11, 1983||President And Fellows Of Harvard College||NMR Sodium images|
|US4421671 *||Jun 18, 1982||Dec 20, 1983||General Electric Company||Rare-earth-doped yttria-gadolinia ceramic scintillators|
|US4425547 *||Jun 9, 1981||Jan 10, 1984||Tokyo Shibaura Denki Kabushiki Kaisha||Nuclear magnetic resonance apparatus having means for compensating a projecting signal|
|US4432907 *||May 5, 1981||Feb 21, 1984||Analytical Radiation Corporation||Diamine acid fluorescent chelates|
|US4442404 *||Dec 1, 1981||Apr 10, 1984||Bergmann Wilfried H||Method and means for the noninvasive, local, in-vivo examination of endogeneous tissue, organs, bones, nerves and circulating blood on account of spin-echo techniques|
|US4450408 *||Dec 11, 1981||May 22, 1984||General Electric Company||Low loss wide band front end for NMR receiver|
|US4472509 *||Jun 7, 1982||Sep 18, 1984||Gansow Otto A||Metal chelate conjugated monoclonal antibodies|
|DE3129906A1 *||Jul 24, 1981||Feb 10, 1983||Schering Ag||Paramagnetische komplexsalze, deren herstellung und verwendung bei der nmr-diagnostik|
|DE3401052A1 *||Jan 11, 1984||Jul 26, 1984||Schering Ag||Diagnostic agent|
|FR2539996A1 *|| ||Title not available|
|GB2137612A *|| ||Title not available|
|1||Brasch, Robert C., et al., "Contrast-Enhanced NMR Imaging: Animal Studies Using Gadolinium DTPA Complex"; AJR 142:625-630, Mar. 1984.|
|2|| *||Brasch, Robert C., et al., Contrast Enhanced NMR Imaging: Animal Studies Using Gadolinium DTPA Complex ; AJR 142:625 630, Mar. 1984.|
|3||Bryden, Charles C.; Reilley, Charles N.; Desreux, Jean F., "Multinuclear NMR Study of Three Aqueous Lanthanide Shift Reagents: Complexes with EDTA and Two Macrocyclic Ligands," American Chemical Society, vol. 97, 1982-Chem. Substance Index, Part 2 of 4, p. 6773; Part 4 of 4, p. 2840; Chemical Abstracts, pp. 616-617.|
|4|| *||Bryden, Charles C.; Reilley, Charles N.; Desreux, Jean F., Multinuclear NMR Study of Three Aqueous Lanthanide Shift Reagents: Complexes with EDTA and Two Macrocyclic Ligands, American Chemical Society, vol. 97, 1982 Chem. Substance Index, Part 2 of 4, p. 6773; Part 4 of 4, p. 2840; Chemical Abstracts, pp. 616 617.|
|5|| *||Chen, Chi wan, et al., Paramagnetic Metalloporphyrins as Potential Contrast Agents in NMR Imaging , Federation of European Biochemical Societies, 1984, vol. 168, No. 1, pp. 70 74.|
|6||Chen, Chi-wan, et al., "Paramagnetic Metalloporphyrins as Potential Contrast Agents in NMR Imaging", Federation of European Biochemical Societies, 1984, vol. 168, No. 1, pp. 70-74.|
|7||Desreux, J. F., "Nuclear Magnetic Resonance Spectroscopy of Lanthanide Complexes with a Tetraacetic Tetraaza Macrocycle, Unusual Conformation Properties," American Chemical Society, 1980, 19, 1319-1324.|
|8|| *||Desreux, J. F., Nuclear Magnetic Resonance Spectroscopy of Lanthanide Complexes with a Tetraacetic Tetraaza Macrocycle, Unusual Conformation Properties, American Chemical Society, 1980, 19, 1319 1324.|
|9|| *||Weinmann, Hanns Joachim, Characteristics of Gadolinium DTPA Complex: A Potential NMR Contrast Agent ; AJR 142:619 624, Mar. 1984.|
|10||Weinmann, Hanns-Joachim, "Characteristics of Gadolinium--DTPA Complex: A Potential NMR Contrast Agent"; AJR 142:619-624, Mar. 1984.|
|11||White, D. W., et al., "A Tris(Dialkylamino)Phosphine with Pyramidal Nitrogens", Journal of the American Chemical Society, 101:17, Aug. 1979, pp. 4921-4925.|
|12|| *||White, D. W., et al., A Tris(Dialkylamino)Phosphine with Pyramidal Nitrogens , Journal of the American Chemical Society, 101:17, Aug. 1979, pp. 4921 4925.|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US4774957 *||Sep 11, 1987||Oct 4, 1988||Kabushiki Kaisha Toshiba||Material for diagnosis by nuclear magnetic resonance imaging|
|US4822594 *||Jan 27, 1987||Apr 18, 1989||Gibby Wendell A||Contrast enhancing agents for magnetic resonance images|
|US4885363 *||Dec 23, 1987||Dec 5, 1989||E. R. Squibb & Sons, Inc.||1-substituted-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane and analogs|
|US4899755 *||May 8, 1985||Feb 13, 1990||The General Hospital Corporation||Hepatobiliary NMR contrast agents|
|US4920195 *||Jan 25, 1988||Apr 24, 1990||Jouko Kankare||Fluorescent lanthanide chelates|
|US4926869 *||Jan 12, 1987||May 22, 1990||The General Hospital Corporation||Method for the diagnosis and treatment of inflammation|
|US4957939 *||Jun 20, 1986||Sep 18, 1990||Schering Aktiengesellschaft||Sterile pharmaceutical compositions of gadolinium chelates useful enhancing NMR imaging|
|US4983376 *||Dec 28, 1988||Jan 8, 1991||Board Of Regents, The University Of Texas System||Triazamacrocyclic NMR contrast agents and methods for their use|
|US5064633 *||Dec 19, 1989||Nov 12, 1991||The Dow Chemical Company||Macrocyclic aminophosphonic acid complexes, their formulations and use|
|US5132409 *||Nov 27, 1989||Jul 21, 1992||Bracco Industria Chimica S.P.A.||Macrocyclic chelating agents and chelates thereof|
|US5155215 *||Nov 7, 1990||Oct 13, 1992||Access Pharmaceuticals Inc.||Polychelating agents for image and spectral enhancement (and spectral shift)|
|US5188816 *||Nov 26, 1991||Feb 23, 1993||Board Of Regents, The University Of Texas System||Using polyazamacrocyclic compounds for intracellular measurement of metal ions using MRS|
|US5190744 *||Mar 9, 1990||Mar 2, 1993||Salutar||Methods for detecting blood perfusion variations by magnetic resonance imaging|
|US5198208 *||Jul 15, 1988||Mar 30, 1993||Nycomed Imaging As||Aminopolycarboxylic acids and derivatives thereof|
|US5208324 *||Jan 26, 1989||May 4, 1993||Nycomed Imaging As||Paramagnetic compounds|
|US5213788 *||Apr 4, 1991||May 25, 1993||Ranney David F||Physically and chemically stabilized polyatomic clusters for magnetic resonance image and spectral enhancement|
|US5230883 *||Jan 27, 1992||Jul 27, 1993||Wisconsin Alumni Research Foundation||Method for localization and treatment of tumors using polylysine complexes|
|US5242683 *||Jul 19, 1990||Sep 7, 1993||Nycomed Imaging As||Contrast media comprising a paramagnetic agent and an iodinated agent for x-ray and mri|
|US5284646 *||Oct 3, 1991||Feb 8, 1994||Advanced Magnetics Inc.||Hepatocyte specific receptor mediated endocytosis type magnetic resonance imaging contrast agents|
|US5310539 *||Apr 15, 1991||May 10, 1994||Board Of Regents, The University Of Texas System||Melanin-based agents for image enhancement|
|US5314681 *||Mar 22, 1993||May 24, 1994||Nycomed Innovation Ab||Composition of positive and negative contrast agents for electron spin resonance enhanced magnetic resonance imaging|
|US5316757 *||Dec 13, 1991||May 31, 1994||Board Of Regents, The University Of Texas System||Synthesis of polyazamacrocycles with more than one type of side-chain chelating groups|
|US5334371 *||Jul 6, 1992||Aug 2, 1994||Schering Aktiengesellschaft||Marcocyclic polyaza bicyclo compounds containing 5 or 6 membered rings, and method for MRI|
|US5342606 *||Nov 19, 1990||Aug 30, 1994||Board Of Regents, The University Of Texas System||Polyazamacrocyclic compounds for complexation of metal ions|
|US5342607 *||Aug 3, 1992||Aug 30, 1994||Advanced Magnetics, Inc.||Receptor mediated endocytosis type magnetic resonance imaging contrast agents|
|US5348954 *||Jan 15, 1990||Sep 20, 1994||Nycomed Imaging As||Heterocyclic chelating agents|
|US5352432 *||Jul 20, 1992||Oct 4, 1994||Advanced Magnetics, Inc.||Hepatocyte specific composition and their use as diagnostic imaging agents|
|US5362476 *||Jul 31, 1992||Nov 8, 1994||Board Of Regents, The University Of Texas System||Alkyl phosphonate polyazamacrocyclic cheates for MRI|
|US5363846 *||May 21, 1990||Nov 15, 1994||The General Hospital Corporation||Method for the diagnosis and treatment of inflammation|
|US5364613 *||Jan 16, 1990||Nov 15, 1994||Sieving Paul F||Polychelants containing macrocyclic chelant moieties|
|US5364614 *||Nov 21, 1990||Nov 15, 1994||Schering Aktiengesellschaft||Cascade polymer bound chelating compounds, their chelates and conjugates, processes for their production, and pharmaceutical agents containing them|
|US5376358 *||Dec 21, 1990||Dec 27, 1994||Mallinckrodt Medical, Inc.||Magnetic resonance imaging agents|
|US5403572 *||Mar 15, 1994||Apr 4, 1995||Schering Aktiengesellschaft||Macrocyclic polyaza compounds containing 5 or 6 membered rings, process for producing them and pharmaceutical media containing them|
|US5417960 *||Feb 3, 1994||May 23, 1995||Guerbet S.A.||Nitrogen-containing cyclic ligands, metallic complexes formed by these ligands, diagnostic compositions containing these complexes and process for the preparation of the ligands|
|US5419893 *||Jan 19, 1993||May 30, 1995||Nycomed Imaging As||Aminopolycarboxylic acids and derivatives thereof for magnetic resonance imaging|
|US5428155 *||May 27, 1994||Jun 27, 1995||Board Of Regents, The University Of Texas System||Synthesis of polyazamacrocycles with more than one type of side-chain chelating groups|
|US5428156 *||Apr 2, 1993||Jun 27, 1995||Associated Universities, Inc.||Synthesis of macrocyclic polyaminocarboxylates and their use for preparing stable radiometal antibody immunoconjugates for therapy, spect and pet imaging|
|US5432178 *||Sep 16, 1993||Jul 11, 1995||Ono Pharmaceutical Co., Ltd.||Amidinophenol derivatives|
|US5439668 *||May 2, 1994||Aug 8, 1995||Nycomed Imaging As||Heterocyclic chelating agents|
|US5474756 *||Dec 20, 1994||Dec 12, 1995||Bracco International B.V.||Method for imaging mammalian tissue using 1-substituted-1,4,7-tricarboxymethyl-1,4,7,10-tetraazacyclododecane and analogs|
|US5480990 *||Dec 22, 1993||Jan 2, 1996||The Dow Chemical Company||Bicyclopolyazamacrocyclocarboxylic acid complexes for use as contrast agents|
|US5494655 *||Sep 14, 1994||Feb 27, 1996||The Regents Of The University Of California||Methods for detecting blood perfusion variations by magnetic resonance imaging|
|US5531978 *||Feb 8, 1993||Jul 2, 1996||Nycomed Imaging As||Aminopolycarboxylic acids and derivatives thereof|
|US5541287 *||Nov 22, 1994||Jul 30, 1996||Neorx Corporation||Pretargeting methods and compounds|
|US5578287 *||Nov 23, 1993||Nov 26, 1996||Neorx Corporation||Three-step pretargeting methods using improved biotin-active agent|
|US5582814 *||Apr 15, 1994||Dec 10, 1996||Metasyn, Inc.||1-(p-n-butylbenzyl) DTPA for magnetic resonance imaging|
|US5587451 *||Oct 7, 1994||Dec 24, 1996||The Dow Chemical Company||Process for preparing polyazamacrocycles|
|US5593659 *||May 30, 1995||Jan 14, 1997||Concat, Ltd.||MRI image enchancement of bone and related tissue using complexes of paramagnetic cations and polyphosphonate ligands|
|US5608060 *||Jun 7, 1993||Mar 4, 1997||Neorx Corporation||Biotinidase-resistant biotin-DOTA conjugates|
|US5630996 *||Sep 16, 1993||May 20, 1997||Neorx Corporation||Two-step pretargeting methods using improved biotin-active agent conjugates|
|US5630997 *||Nov 8, 1994||May 20, 1997||Board Of Regents, The University Of Texas System||Phosphorylated polyazamacrocyclic compounds for complexation of metal ions|
|US5648063 *||Aug 4, 1993||Jul 15, 1997||Schering Aktiengesellschaft||Sterile composition comprising a chelate complex for magnetic resonance imaging|
|US5650136 *||Dec 2, 1994||Jul 22, 1997||Schering Aktiengesellschaft||Cascade polymer bound complexing compounds, their complexes and conjugates, processes for their production, and pharmaceutical agents containing them|
|US5674470 *||Jun 6, 1995||Oct 7, 1997||Bracco Diagnostics Inc.||Method for imaging mammalian tissue using 1-substituted- 4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododecane and analogs|
|US5679323 *||May 18, 1995||Oct 21, 1997||Advanced Magnetics, Inc.||Hepatocyte-specific receptor-mediated endocytosis-type compositions|
|US5702683 *||Jan 22, 1991||Dec 30, 1997||The United States Of America As Represented By The United States Department Of Energy||Nuclear magnetic resonance contrast agents|
|US5739294 *||Aug 3, 1994||Apr 14, 1998||The Dow Chemical Company||Bicyclopol yazamacrocyclophosphonic acid complexes for use as contrast agents|
|US5750660 *||Jul 15, 1996||May 12, 1998||The Dow Chemical Company||Bicyclopolyazamacrocyclophosphonic acid half esters|
|US5792444 *||Oct 22, 1993||Aug 11, 1998||The General Hospital Corporation||Labeled chemotactic peptides to image focal sites of infection or inflammation|
|US5811077 *||Dec 18, 1996||Sep 22, 1998||Nihon Medi-Physics Co., Ltd.||Method of NMR imaging|
|US5833947 *||Feb 23, 1996||Nov 10, 1998||The Regents Of The University Of California||Magnetic resonance imaging|
|US5846519 *||Jun 6, 1995||Dec 8, 1998||Bracco Diagnostics Inc.||Method for imaging mammalian tissue using 1-substituted-1,4,7-tricarboxymethyl-1,4,7,10-tetraazacyclododecane and analogs|
|US5847121 *||Dec 13, 1995||Dec 8, 1998||Neorx Corporation||Production of nitro-benzyl-dota via direct peptide cyclization|
|US5914095 *||Oct 7, 1991||Jun 22, 1999||Salutar, Inc.||Polychelants containg amide bonds|
|US5955605 *||Aug 12, 1996||Sep 21, 1999||Neorx Corporation||Biotinidase resistant biotin-DOTA conjugates|
|US6022966 *||Nov 22, 1993||Feb 8, 2000||Neorx Corporation||Pretargeting methods and compounds|
|US6093382 *||May 16, 1998||Jul 25, 2000||Bracco Research Usa Inc.||Metal complexes derivatized with folate for use in diagnostic and therapeutic applications|
|US6143274 *||Jun 6, 1995||Nov 7, 2000||Tweedle; Michael F.||Method for imaging and radiopharmaceutical therapy using 1-substituted-4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododecane and analogs|
|US6221334||Jan 3, 2000||Apr 24, 2001||Bracco Research Usa, Inc.||Metal complexes derivatized with folate for use in diagnostic and therapeutic applications|
|US6287536||Jan 27, 1997||Sep 11, 2001||Neorx Corporation||Two-step pretargeting methods using improved bidtin-active agent conjugates|
|US6358490||May 21, 1999||Mar 19, 2002||Neorx Corporation||Three-step pretargeting methods and compounds|
|US6576222||Oct 11, 2001||Jun 10, 2003||Schering Aktiengesellschaft||Cascade polymer bound complexing compounds, their complexes and conjugates, process for their production and pharmaceutical agents containing them|
|US6676929||Dec 20, 2001||Jan 13, 2004||Epix Medical, Inc.||Diagnostic imaging contrast agents with extended blood retention|
|US6709652||Aug 1, 2001||Mar 23, 2004||Neorx Corporation||Pretargeting methods and compounds|
|US6767531||Dec 11, 2001||Jul 27, 2004||Neorx Corporation||High dose radionuclide complexes for bone marrow suppression|
|US6797257||Oct 12, 2001||Sep 28, 2004||The Board Of Trustees Of The University Of Illinois||Paramagnetic polymerized protein microspheres and methods of preparation thereof|
|US6855309||Dec 11, 2002||Feb 15, 2005||Schering, Ag||Cascade polymer bound complexing compounds, their complexes and conjugates, processes for their production, and pharmaceutical agents containing them|
|US7011815||Jan 30, 2003||Mar 14, 2006||Epix Pharmaceuticals, Inc.||Diagnostic imaging contrast agents with extended blood retention|
|US7060250||Jan 12, 2004||Jun 13, 2006||Epix Pharmaceuticals, Inc.||Diagnostic imaging contrast agents with extended blood retention|
|US7070759||Jan 24, 2005||Jul 4, 2006||Neorx Corporation||High dose radionuclide complexes for bone marrow suppression|
|US7078013||Feb 10, 2004||Jul 18, 2006||Aletheon Pharmaceuticals, Inc.||Pretargeting methods and compounds|
|US7094885||Jun 20, 2003||Aug 22, 2006||Neorx Corporation||Skeletal-targeted radiation to treat bone-associated pathologies|
|US7097823||Feb 23, 2004||Aug 29, 2006||Neorx Corporation||High dose radionuclide complexes for bone marrow suppression|
|US7115720||Jul 8, 2003||Oct 3, 2006||Neorx Corporation||Therapeutic and diagnostic compounds, compositions, and methods|
|US7186397||Dec 30, 2000||Mar 6, 2007||Bracco International B.V.||Metal complexes derivatized with folate for use in diagnostic and therapeutic applications|
|US7208139||Sep 30, 2004||Apr 24, 2007||Schering Ag||Cascade polymer bound complexing compounds, their complexes and conjugates, processes for their production, and pharmaceutical agents containing them|
|US7229606||Jan 12, 2004||Jun 12, 2007||Epix Pharmaceuticals, Inc.||Diagnostic imaging contrast agents with extended blood retention|
|US7378077||Jul 12, 2006||May 27, 2008||Poniard Pharmaceuticals, Inc.||High dose radionuclide complexes for bone marrow suppression|
|US7385042||Jul 13, 2006||Jun 10, 2008||Poniard Pharmaceuticals, Inc.||Therapeutic and diagnostic compounds, compositions, and methods|
|US7399460||Sep 25, 2006||Jul 15, 2008||Bracco International B.V.||Metal complexes derivatized with folate for use in diagnostic and therapeutic applications|
|US7408046||Jun 30, 2004||Aug 5, 2008||Poniard Pharmaceuticals, Inc.||Treatment of bone-associated cancers|
|US7605239||Feb 22, 2006||Oct 20, 2009||Poniard Pharmaceuticals, Inc.||Skeletal-targeted radiation to treat bone-associated pathologies|
|US7691985||Mar 6, 2008||Apr 6, 2010||Poniard Pharmaceuticals, Inc.||Skeletal-targeted radiation to treat bone-associated pathologies|
|US7696331||Jun 19, 2008||Apr 13, 2010||Poniard Pharmaceuticals, Inc.||High dose radionuclide complexes for bone marrow treatment|
|US8017105||Jun 22, 2006||Sep 13, 2011||Lantheus Medical Imaging, Inc.||Diagnostic imaging contrast agents with extended blood retention|
|US8369930||Jun 16, 2010||Feb 5, 2013||MRI Interventions, Inc.||MRI-guided devices and MRI-guided interventional systems that can track and generate dynamic visualizations of the devices in near real time|
|US8388931||Feb 27, 2009||Mar 5, 2013||Marcos Lopez||99m Tc-labeled triphenylphosphonium derivative contrasting agents and molecular probes for early detection and imaging of breast tumors|
|US8388936||Feb 23, 2009||Mar 5, 2013||Mcw Research Foundation, Inc.||In vivo mitochondrial labeling using positively-charged nitroxide enhanced and gadolinium chelate enhanced magnetic resonance imaging|
|US8394356||Aug 29, 2011||Mar 12, 2013||Lantheus Medical Imaging, Inc.||Diagnostic imaging contrast agents with extended blood retention|
|US8396532||Jun 16, 2010||Mar 12, 2013||MRI Interventions, Inc.||MRI-guided devices and MRI-guided interventional systems that can track and generate dynamic visualizations of the devices in near real time|
|US8610431||Jan 25, 2011||Dec 17, 2013||Baker Hughes Incorporated||NMR contrast logging|
|US8669236||May 12, 2006||Mar 11, 2014||The General Hospital Corporation||Biotinylated compositions|
|US8768433||Dec 21, 2012||Jul 1, 2014||MRI Interventions, Inc.||MRI-guided devices and MRI-guided interventional systems that can track and generate dynamic visualizations of the devices in near real time|
|US8825133||Jan 24, 2013||Sep 2, 2014||MRI Interventions, Inc.||MRI-guided catheters|
|US8886288||Jan 10, 2013||Nov 11, 2014||MRI Interventions, Inc.||MRI-guided devices and MRI-guided interventional systems that can track and generate dynamic visualizations of the devices in near real time|
|US20120148492 *||Aug 19, 2010||Jun 14, 2012||Fujifilm Ri Pharma Co., Ltd.||Bisphosphonic acid derivative and compound thereof labeled with radioactive metal nuclide|
|USRE35152 *||Jan 12, 1987||Feb 6, 1996||The General Hospital Corporation||Method for the diagnosis and treatment of inflammation|
|DE3709851A1 *||Mar 24, 1987||Oct 6, 1988||Silica Gel Gmbh Adsorptions Te||Nmr-diagnostische fluessigkeitszusammensetzungen|
|EP0325762A1 *||Dec 16, 1988||Aug 2, 1989||BRACCO S.p.A.||Macrocyclic chelating agents and chelates thereof|
|EP0670167A1||Aug 3, 1989||Sep 6, 1995||Advanced Magnetics, Inc.||Receptor mediated endocytosis type diagnostic agents|
|EP1602649A2||Dec 18, 1998||Dec 7, 2005||Bracco Imaging, S.P.A.||1,4,7,10-tetraazacyclododecane-1,4-diacetic acid derivatives as chelating agents|
|EP2242515A2 *||Feb 18, 2009||Oct 27, 2010||Guerbet||Process for preparing a pharmaceutical formulation of contrast agents|
|EP2591807A1 *||Feb 18, 2009||May 15, 2013||Guerbet||Process for preparing a pharmaceutical formulation of contrast agents|
|WO1987004351A1 *||Jan 12, 1987||Jul 30, 1987||Gen Hospital Corp||Method for the diagnosis and treatment of inflammation|
|WO1989005802A1 *||Dec 16, 1988||Jun 29, 1989||Bracco Ind Chimica Spa||Macrocyclic chelating agents and chelates thereof|
|WO1990001900A1 *||Aug 17, 1989||Mar 8, 1990||Univ Connecticut||Carrier system and method for enhancement of magnetic resonance imaging|
|WO1990013256A1 *||May 2, 1990||Nov 5, 1990||Wisconsin Alumni Res Found||Method for localization and treatment of tumors and complexes therefor|
|WO1992019264A1 *||May 1, 1992||Nov 12, 1992||Univ New Mexico||Biomodulators as universal imaging agents|
| || |
|U.S. Classification||424/9.363, 436/806, 436/173, 534/16, 534/15|
|International Classification||A61K49/06, C07F9/6515, A61K49/00, C07F9/6524, A61K51/04, C07D257/02, C07D255/02|
|Cooperative Classification||Y10T436/24, Y10S436/806, C07D257/02, C07F9/6524, C07F9/6515, A61K49/06, A61K2123/00, A61K51/04, C07D255/02|
|European Classification||C07D257/02, C07F9/6524, A61K49/06, A61K51/04, C07F9/6515, C07D255/02|
|Apr 6, 1999||FP||Expired due to failure to pay maintenance fee|
Effective date: 19990127
|Jan 24, 1999||LAPS||Lapse for failure to pay maintenance fees|
|Aug 18, 1998||REMI||Maintenance fee reminder mailed|
|Jul 9, 1996||DI||Adverse decision in interference|
Effective date: 19960206
|Jul 11, 1994||FPAY||Fee payment|
Year of fee payment: 8
|Jul 18, 1990||FPAY||Fee payment|
Year of fee payment: 4
|Oct 18, 1984||AS||Assignment|
Owner name: BOARD OF REGENTS, THE UNIERSITY OF TEXAS SYSTEM 20
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:SHERRY, A. DEAN;REEL/FRAME:004326/0785
Effective date: 19841009